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Abstract:

A stable anaesthetic composition is described which is particularly
suitable for use in cats and dogs. The composition comprises an aqueous
solution of an anaesthetically effective amount of a water soluble
cyclodextrin or a cyclodextrin derivative complex of alfaxalone and a
buffer, excluding phosphate buffer pH 7.0, 0.1M mixed as defined in the
British Pharmacopoeia 1998, such that the pH of the solution is from
6.0-8.0.

Claims:

1. An anaesthetic composition, comprising: an aqueous solution of an
anaesthetically effective amount of a water soluble cyclodextrin or a
cyclodextrin derivative complex of alfaxalone and buffer effective to
stabilise the alfaxalone and provide a pH in the composition of from
about 6.5 to about 7.0, wherein crystalline material does not form in the
composition within about 7 days when stored at 40.degree. C., and the
water soluble cyclodextrin or cyclodextrin derivative is 2-hydroxypropyl
beta-cyclodextrin, and the concentration of alfaxalone is 7-15 mg/mL.

2. The anaesthetic composition of claim 1, wherein the pH in the
composition is from 6.5 to 7.0.

3. A sterile ready-to-use dosage of an anaesthetic comprising a package
which includes an anaesthetic composition as claimed in claim 1.

4. A sterile ready-to-use dosage of an anaesthetic further including one
or more antimicrobial agents.

5. A sterile dosage of an anaesthetic composition, comprising: a first
package containing in dry form, an anaesthetically effective amount of a
water soluble cyclodextrin or a cyclodextrin derivative complex of
alfaxalone and a buffer effective to stabilise the alfaxalone; and a
second package of sterile water, the buffer being selected such that a
solution formed by dissolving the contents of the first package with
contents of the second package has a pH of from about 6.5 to about 7.0,
wherein crystalline material does not form in the composition within
about 7 days when stored at 40.degree. C., the water soluble cyclodextrin
or cyclodextrin derivative is 2-hydroxypropyl beta-cyclodextrin, and the
concentration of alfaxalone is 7-15 mg/mL in the solution formed by
dissolving the contents of the first package with contents of the second
package.

6. The sterile dosage of claim 5, wherein the contents of the second
package has a pH of from 6.5 to 7.0.

7. A sterile dosage of an anaesthetic composition, comprising: a first
package containing in dry form, an anaesthetically effective amount of a
water soluble cyclodextrin or a cyclodextrin derivative complex of
alfaxalone; and a second package containing a sterile aqueous solution of
a buffer, the buffer being selected such that a solution formed by
dissolving the contents of the first package with contents of the second
package has a pH of from 6.5-7.0 and the buffer is effective to stabilise
the alfaxalone, wherein crystalline material does not form in the
composition within about 7 days when stored at 40.degree. C., the water
soluble cyclodextrin or cyclodextrin derivative is 2-hydroxypropyl
beta-cyclodextrin, and the concentration of alfaxalone is 7-15 mg/mL in
the solution formed by dissolving the contents of the first package with
contents of the second package.

8. The sterile dosage of claim 7, wherein the contents of the second
package has a pH of from 6.5 to 7.0.

9. A sterile dosage of an anaesthetic composition, comprising: a package
containing in dry form for reconstitution with sterile water; an
anaesthetically effective amount of a water soluble cyclodextrin or a
cyclodextrin derivative complex of alfaxalone; and a buffer, the buffer
being selected such that a solution formed by dissolving the contents of
the package with sterile water has a pH of from about 6.5 to about 7.0
and the buffer is effective to stabilise the alfaxalone, wherein
crystalline material does not form in the composition within about 7 days
when stored at 40.degree. C., the water soluble cyclodextrin or
cyclodextrin derivative is 2-hydroxypropyl beta-cyclodextrin, and the
concentration of alfaxalone is 7-15 mg/mL in the solution formed by
dissolving the contents of the first package with contents of the second
package.

10. The sterile dosage of claim 9, wherein the contents of the package
has a pH of from 6.5 to 7.0.

11. A method of anaesthetising warm-blooded animals comprising
administering to said animals an anaesthetically effective amount of a
composition as claimed in claim 1.

12. A method of anaesthetising warm-blooded animals comprising
administering to said animals an anaesthetically effective amount of the
dosage of claim 3.

Description:

TECHNICAL FIELD

[0001] This invention relates to anaesthetic compositions for use in
warm-blooded animals including birds and mammals, reptiles, fish and
amphibians and in particular to alfaxalone-based compositions in which
the alfaxalone is water-solubilised through the formation of a complex
with a cyclodextrin or a cyclodextrin derivative.

BACKGROUND ART

[0002] 3α-hydroxy-5α-pregnane-11,20-dione (alfaxalone) is a
known anaesthetic for use in a variety of animals. Owing to the fact that
in use, alfaxalone has a wide safety margin, rapid induction, high
potency, absence of nausea and rapid progress to ambulation, it has been
regarded as a very useful anaesthetic. However, the substance is quite
water insoluble and therefore must be solubilised for effective
parenteral use. Solubilisation in saline has been achieved commercially
using polyethoxylated castor oil in combination with a small amount of
alfadolone acetate
(21-acetoxy-3α-hydroxy-5α-pregnane-11,20-dione), a steroid
which is half as potent an anaesthetic agent as alfaxalone. Nevertheless,
its practical usefulness in mammals has been severely limited since these
alfaxalone-based compositions invoke a histamine response in a number of
species when administered parenterally.

[0003] Because of alfaxalone's efficacy, the present inventors have sought
to meet the problem of providing an alfaxalone-based composition which is
both anaesthetically effective and able to be administered parenterally
to mammals without invoking a histamine response.

[0004] It is also evident that for practical reasons it is desirable that
formulations of water soluble cyclodextrin or cyclodextrin derivative
complexes of alfaxalone are presented as ready-to-use solutions. That is
no reconstitution is required prior to use. As used in this
specification, "complex" is to be understood as referring to the water
soluble moiety formed by the hydrophilic/hydrophobic interaction between
alfaxalone and cyclodextrin or cyclodextrin derivative.

[0005] It may be expected that owing to the common use of phosphate
buffer, 0.1M mixed pH 7.0 (BP 1998) in parenteral formulations,
cyclodextrin or cyclodextrin derivative complexes of alfaxalone should be
suitable for use with this buffer. In fact it has been found by the
present inventors that in formulating a ready-to-use anaesthetic
composition, there is a fundamental problem in that formulations of the
water soluble cyclodextrin or cyclodextrin derivative complexes of
alfaxalone with pH 7.0 phosphate buffer are unstable. By unstable it is
meant that a crystalline material was formed in a representative
formulation within about 7 days when it was stored at 40° C. The
presence of such crystals precludes the acceptability in use of such a
formulation.

DISCLOSURE OF INVENTION

[0006] In seeking to provide a stable ready-to-use formulation of
cyclodextrin or cyclodextrin derivative complexes of alfaxalone, the
present inventors have established that the nature of the buffer used is
important.

[0007] Accordingly in a first aspect, the present invention consists in a
stable anaesthetic composition which comprises an aqueous solution of an
anaesthetically effective amount of a water soluble cyclodextrin or a
cyclodextrin derivative complex of alfaxalone and a buffer, excluding
phosphate buffer pH 7.0, 0.1M mixed as defined in the British
Pharmacopoeia 1998, such that the pH of the solution is from 4.5-8.0.

[0008] In a second aspect, the present invention further consists in a
method of anaesthetising warm-blooded animals including birds and
mammals, reptiles, fish and amphibians comprising administering to said
animals an anaesthetically effective amount of a stable anaesthetic
composition which comprises an aqueous solution of an anaesthetically
effective amount of a water soluble cyclodextrin or a cyclodextrin
derivative complex of alfaxalone and a buffer such that the pH of the
solution is from 4.5-8.0.

[0009] In a third aspect, the present invention still further consists in
a sterile ready-to-use dosage of an anaesthetic comprising a package
which includes an aqueous solution of an anaesthetically effective amount
of a water soluble cyclodextrin or a cyclodextrin derivative complex of
alfaxalone and a buffer, excluding phosphate buffer pH 7.0, 0.1M mixed as
defined in the British Pharmacopoeia 1998, such that the pH of the
solution is from 4.5-8.0 and optionally one or more antimicrobial agents.

[0010] In a fourth aspect, the present invention provides a sterile dosage
of an anaesthetic composition comprising a first package containing in
dry form, an anaesthetically effective amount of a water soluble
cyclodextrin or a cyclodextrin derivative complex of alfaxalone and a
buffer, excluding phosphate buffer pH 7.0, 0.1M mixed as defined in the
British Pharmacopoeia 1998, and a second package of sterile water, the
buffer being selected such that a solution formed by dissolving the
contents of the first package with contents of the second package has a
pH from 4.5-8.0.

[0011] In a fifth aspect, the present invention also provides a sterile
dosage of an anaesthetic composition comprising a first package
containing in dry form, an anaesthetically effective amount of a water
soluble cyclodextrin or a cyclodextrin derivative complex of alfaxalone,
and a second package containing a sterile aqueous solution of a buffer,
excluding phosphate buffer pH 7.0, 0.1M mixed as defined in the British
Pharmacopoeia 1998, the buffer being selected such that a solution formed
by dissolving the contents of the first package with contents of the
second package has a pH from 4.5-8.0.

[0012] In a sixth aspect, the present invention still further provides a
sterile dosage of an anaesthetic composition comprising a package
containing in dry form for reconstitution with sterile water, an
anaesthetically effective amount of a water soluble cyclodextrin or a
cyclodextrin derivative complex of alfaxalone and a buffer, excluding
phosphate buffer pH 7.0, 0.1M mixed as defined in the British
Pharmacopoeia 1998, and a second package of sterile water, the buffer
being selected such that a solution formed by dissolving the contents of
the package with sterile water has a pH from 4.5-8.0.

[0013] Throughout this specification the word "comprise", or variations
such as "comprises" or "comprising", will be understood to imply the
inclusion of a stated element, integer or step, or group of elements,
integers or steps, but not the exclusion of any other element, integer or
step, or group of elements, integers or steps.

[0014] Complexes of alfaxalone with a cyclodextrin or a cyclodextrin
derivative may be readily formed by adding an appropriate amount of
alfaxalone to a preformed aqueous solution of cyclodextrin or
cyclodextrin derivative. Formation of the complex occurs spontaneously
which may then be isolated by drying. This process is further described
in U.S. Pat. No. 4,727,064. Whilst a variety of cyclodextrins or
cyclodextrin derivatives may be used, it is preferred to use
2-hydroxypropyl beta-cyclodextrin as the complexing agent.

[0015] Alternatively, the drying step may be omitted. In this case, the
requisite amounts of the buffer components are added to the solution of
the alfaxalone complex with water being finally added as required to give
the desired concentration of alfaxalone in the solution.

[0016] A buffer is used in combination with the alfaxalone complex. This
buffer must provide a pH for the composition of from 4.5-8.0, preferably
6.0-7.0, most preferably about 6.8.

[0017] Whilst a variety of buffer compositions may be used,
phosphate-based buffers are preferred, excluding phosphate buffer pH 7.0,
0.1M mixed (BP 1998). This excluded buffer is formed by dissolving 1.361
g of potassium dihydrogen orthophosphate in sufficient water to produce
100 mL, the pH being adjusted by using a 3.5% w/v solution of disodium
hydrogen orthophosphate. Particularly preferred are acid-phosphate
buffers, such as citro-phosphate buffer pH 6.5. This buffer is defined in
the British Pharmacopoeia 1998 as a mixture of 29.0 mL of 0.1M citric
acid with sufficient 0.2M anhydrous disodium hydrogen orthophosphate to
produce 100 mL. The amount of buffer used relative to the alfaxalone
complex may be varied.

[0018] In a preferred form, the compositions of the invention are
presented in sterile form packed in vials ready-to-use. Whilst in a
variety of animals, the compositions will be administered parenterally,
in the case of fish, the composition may be mixed in the water containing
the fish. In this way, the alfaxalone passes across the gills where it is
absorbed systemically to produce the requisite anaesthetic/tranquillising
effect. Naturally, the water to which the composition is added will
depend on whether the fish are fresh or salt water species.

[0019] Other animals that may be effectively anaesthetised with
compositions of the invention are mammals including marsupials, sheep,
horses, pigs, goats, deer, cattle, dogs and cats. It is particularly
useful in dogs as the compositions do not invoke the histamine response
of previously known alfaxalone compositions.

[0020] The person skilled in the art will appreciate that various
antimicrobial agents known in the art may be included in the compositions
of the invention to provide an appropriate level of preservation. It will
also be appreciated that the compositions of the invention may be
sterilised for parenteral use by various methods including autoclaving
after being filled into vials or by filtration through a 0.22 μm
filter into sterile vials.

[0021] The amount of alfaxalone included in a composition will be
determined by the nature of the animal to be anaesthetised. For guidance,
a level of 1-100 mg/mL, preferably 5-25 mg/mL, most preferably 7-15 mg/mL
may be appropriate.

[0022] Stability on storage of the compositions of the invention is an
important attribute. In general terms, the compositions will have a shelf
life of at least 6 months when stored at below 25° C., preferably
at least 6 months when stored below 30° C., most preferably at
least 2 years when stored below 30° C.

MODES FOR CARRYING OUT THE INVENTION

[0023] In order to better understand the nature of this invention, a
number of illustrative examples will now be described.

Preparation of Complex

Alfaxalone-Cyclodextrin Powder

[0024] 1. Add 435 grams of hydroxypropyl-beta cyclodextrin (HPCD) to 1 L
of distilled water and stir to dissolve. [0025] 2. Add with stirring to
the solution 30 g of alfaxalone. [0026] 3. Add sufficient dissolved HPCD
to adjust the content of alfaxalone to 120 mg per gram of powder when
dried. [0027] 4. Dry the solution.

Alfaxalone:HPCD Citro-Phosphate Solution

[0027][0028] 1. Add 435 g of hydroxypropyl-beta cyclodextrin (HPCD) in
1 L of water for injection (BP) and stir to dissolve. [0029] 2. Add with
stirring to the solution 30 g alfaxalone. [0030] 3. Add citric acid to
the solution from with stirring on the basis of 6.09 g citric acid per L
of solution. [0031] 4. Add sodium phosphate to the solution with stirring
on the basis of 20.08 disodium hydrogen orthophosphate anhydrous per L of
solution. [0032] 5. Add water for injection (BP) to give a final
concentration of alfaxalone of 10 mg/mL.

Determination of Stability

[0033] A composition was prepared as described above, filtered through a
0.22 μm filter under Class A laminar flow conditions and filled,
sealed and capped into clear sterile clear type I glass 13 mL vials with
chlorobutyl rubber and aluminium crimp seals. The vials were autoclaved
at 121° C. for 20 min with 2 min drying cycle. The composition
packed in the vials was subjected to stability testing with the results
obtained being set out below in Table 1.

[0034] The product is stable following storage at 4° C. for a
period of at least 52 weeks with no chemical or physical deterioration
evident.

[0035] A composition was prepared as described above, filtered through a
0.22 μm filter under Class A laminar flow conditions and filled,
sealed and capped into clean sterile clear type I glass 13 mL vials with
chlorobutyl rubber and aluminium crimp seals. The composition packed in
the vials was subjected to stability testing with the results obtained
being set out below in Table 2.

[0036] The product is stable for 15 months at 30° C., 40° C.
and 50° C. which indicates that the product would have an expected
shelf life of at least 30 months if stored at 30° C. or lower.

[0037] Clinical Evaluation

[0038] A trial was undertaken to evaluate the efficacy of a composition of
the invention in a group of 42 cats. The composition used was a sterile
solution of Alfaxalone:HPCD diluted in citro-phosphate buffer pH 6.5 (BP
1998) containing the equivalence of 10 mg/mL alfaxalone.

[0039] A summary of the dose range used, route of administration, mean
recovery time to head lift and sternal recumbency after anaesthesia and
mean surgery time is presented in Table 3.

[0040] The mean dose of alfaxalone, where alfaxalone was used as the sole
anaesthetic, was 4.5 mg/kg for induction and a mean total dose of 5.8
mg/kg bodyweight. The mean recovery time was 30 minutes to head lift and
44 minutes to sternal recumbency. The mean procedure time was 9 minutes.

[0042] Four of the 42 cats were reported to be "jumpy on recovery", one
cat vomited on recovery and one cat had a prolonged time to head lift but
was then on its feet shortly after lifting its head.

[0043] These results clearly indicate that the compositions of the
invention are clinically efficacious.

[0044] It will be appreciated by persons skilled in the art that numerous
variations and/or modifications may be made to the invention as shown in
the specific embodiments without departing from the spirit or scope of
the invention as broadly described. The present embodiments are,
therefore, to be considered in all respects as illustrative and not
restrictive.